Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders

ABSTRACT

Drug-delivery systems such as drug-delivery stents having an anti-proliferative agent such as everolimus and an anti-flammatory agent such as clobetasol are provided. Also disclosed are methods of treating a vascular impairment such as restenosis or vulnerable plaque.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a drug combination including ananti-proliferative drug such as everolimus and an anti-inflammatoryagent such as clobetasol for the treatment of a disorder such asrestenosis and vulnerable plaque.

2. Description of the Background

Plaques have been associated with stenosis and restenosis. Whiletreatments of plaque-induced stenosis and restenosis have advancedsignificantly over the last few decades, the morbidity and mortalityassociated with vascular plaques have remained significant. Recent worksuggests that plaque may generally fall into one of two differentgeneral types: standard stenotic plaques and vulnerable plaques.Stenotic plaque, which is sometimes referred to as thrombosis-resistantplaque, can generally be treated effectively by the known intravascularlumen opening techniques. Although plaques induce stenoses, theseatherosclerotic plaques themselves are often a benign and are aneffectively treatable disease.

Unfortunately, as plaque matures, narrowing of a blood vessel by aproliferation of smooth muscle cells, matrix synthesis, and lipidaccumulation may result in formation of a plaque which is quitedifferent than a standard stenotic plaque. Such atherosclerotic plaquebecomes thrombosis-prone, and can be highly dangerous. Thisthrombosis-prone or vulnerable plaque may be a frequent cause of acutecoronary syndrome.

While the known procedures for treating plaque have gained wideacceptance and shown good efficacy for treatment of standard stenoticplaques, they may be ineffective (and possibly dangerous) whenthrombotic conditions are superimposed on atherosclerotic plaques.Specifically, mechanical stresses caused by primary treatments likepercutaneous transluminal intervention (PTI), such as stenting, mayactually trigger release of fluids and/or solids from a vulnerableplaque into the blood stream, thereby potentially causing a coronarythrombotic occlusion. For example, rupture of the fibrous cap thatoverlies the thrombogenic necrotic core is presently believed to play animportant role in acute ischemic events, such as stroke, transientischemic attack, myocardial infarction, and unstable angina (Virmani R,et al. Arterioscler Thromb Vasc Biol. 20: 1262-1275 (2000)). There isevidence that fibrous cap can be ruptured during stent deployment. Humandata from various sources have indicated that lipid rich and/orpositively remodeled and/or echolucent lesions in sysmptomatic coronaryatherosclerosis have higher likelihood for restenosis (See, for example,J. Am. Coll. Cardiol. 21(2):298-307 (1993); Am. J. Cardiol. 89(5):505(2002); Circ. 94(12):3098-102 (1996)). Therefore, there is a need forthe treatment of vulnerable plaques and restenosis.

The embodiments of the present invention address these and other needs.

SUMMARY OF THE INVENTION

Described herein are a drug-delivery system and the method of using thedrug-delivery system. The drug-delivery system has two or more drugs fortreating a vascular disorder or a related disorder. The drugs can be acombination of at least one anti-proliferative agent, at least oneanti-inflammatory agent, and optionally a third bioactive agent. In oneembodiment, the anti-proliferative agent can be a drug such aseverolimus, and the anti-inflammatory agent can be a drug such asclobetasol.

Methods of treating of preventing vascular disorders such as restenosisand vulnerable plaque are also disclosed by administering to the patienta combination of at least one anti-proliferative agent, at least oneanti-inflammatory agent, and optionally a third bioactive agent. Themode of delivery can be local or systemic.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows the results of 28 day quantitative coronary angioplasty(QCA) of a porcine implant study on drug-delivery systems describedherein.

FIG. 2 shows 28 day histology data of a porcine implant study ondrug-delivery systems described herein.

FIG. 3 shows the 28 day morphometry data of a porcine implant study ondrug-delivery systems described herein.

DETAILED DESCRIPTION Anti-Proliferative Agents and Anti-InflammatoryAgents

In accordance with one embodiment, described herein are a drug-deliverysystem and the method of using the drug-delivery system. The term“treatment” includes prevention, reduction, delay or elimination of thevascular disorder. In some embodiments, treatment also includesrepairing damage caused by the dirorder and/or the mechanicalintervention. The drug-delivery system has two or more drugs fortreating a vascular disorder or a related disorder. The drugs can be acombination of at least one anti-proliferative agent, at least oneanti-inflammatory agent, and optionally a third bioactive agent.

In one embodiment, the composition described herein includes aneffective amount of at least one anti-inflammatory agent and aneffective amount of an anti-proliferative agent. In another embodiment,the composition described herein includes an effective amount of anagent which is effective both as an anti-inflammatory agent and as ananti-proliferative agent.

In some embodiments, the anti-proliferative agent can be everolimus(available under the trade name Certican™, Novartis Pharma A G,Germany), and the anti-inflammatory agent can be clobetasol (availableunder the trade name Temovate™, Glaxosmithkline, UK).

The anti-proliferative agent and the anti-inflammatory agent can be inthe form of a coating with and/or without a polymer matrix on a medicaldevice or at elast one of the agents can be administered in a separatedose form such as bolus dose of a free drug, optionally withfluoroscopic dye, or bolus dose of a gel encapsulating a drug. Thedrug-delivery system or composition may further include a third agentsuch as a high-density lipoproptein mimetic (HDL-mimetic). For example,an anti-inflammatory agent such as clobetasol can be delivered alongwith the catheter based delivery of a HDL-mimetic while everolimus isadministered by a stent.

The drug-delivery system or composition disclosed herein can be used totreat or prevent a disorder such as thrombosis, high cholesterol,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, restenosis and progression ofatherosclerosis in patient subsets including type I diabetics, type IIdiabetics, metabolic syndrome and syndrome X, vulnerable lesionsincluding those with thin-capped fibroatheromatous lesions, systemicinfections including gingivitis, hellobacteria, and cytomegalovirus, andcombinations thereof.

Inflammation in Stenting a Vessel

A common disorder in association with mechanical modification of avessel, such as by a balloon or stenting is restenosis. A number ofcellular mechanisms have been proposed that lead to restenosis of avessel. Two of these mechanisms are (1) the migration and proliferationof smooth muscle cells to and at the site of injury, and (2) the acuteand chronic inflammatory response to injury and foreign body presence.

Inflammation is a defensive, biological response to injury, infection oran abrupt change in tissue homeostasis. Inflammation can occur anywherein the body, and most of the time is confined to that part of the body.Well-known indicators of inflammation are pain, redness, warmth,swelling, and loss of function. In nature, inflammatory responses aredesigned to destroy, dilute and isolate injurious agents and then leadto recovery and repair of the affected tissue. The intensity of aninflammatory response can vary from one that is self-limiting, whichrequires minor therapeutic intervention, to one that is lifethreatening, which requires intense intervention. One drawback of theinflammatory process is its ability to become progressive, meaningtissue damage continues after the stimulus is neutralized or removed.

Vascular inflammation is the first stage of the inflammatory response,developing after the initial contact with the stimulus and continuingsometimes for several days. The presence of a stimulatory agent in theblood or in the tissue triggers the body's response through endothelialcells. The endothelial cell layer is the innermost layer of largervessels and the only cell layer of the smallest vessels, thecapillaries. Endothelial cells produce substances called chemokines thatattract neutrophils and other white blood cells to the site of injury.Within the site, neutrophils and endothelium relay information back andforth across cell membranes through presentation of adhesion moleculesand cytokines. Cellular cross-talk promotes physical interaction betweenthe “inflamed” neutrophil and the “inflamed” endothelium.

Another important pathological feature of vascular inflammation isendothelial cell swelling. This action reduces the functional vesseldiameter such that the speed of blood flow falls significantly and thevessel becomes congested. When these conditions predominate, inflamedneutrophils are induced to plug the vessel. As a result, endothelialcells lose their tight connections allowing neutrophils to transmigrateinto the surrounding tissue.

Within hours of the initial stimulus, neutrophils begin to enter thetissue and may continue transmigration for many days. The appearance ofinflammatory cells in the surrounding tissue marks the beginning oftissue damage. In some inflammatory conditions, tissue damage is causedby direct injury of the vessels and amplified by the subsequentrecruitment of neutrophils into the tissue.

Activated by local mediators, neutrophils and tissue macrophages aretriggered to release agents that destroy toxins and clean up dead cellsin the area. Unfortunately, these same agents also cause collateraldamage to healthy cells, which further extends the borders of theinitial tissue destruction.

Tissue repair is the third and final stage of inflammation. It may takeseveral days for tissue destruction to reach full intensity beforetapering off. Until then, the tissue repair process that consists ofgrowth of new blood vessels and entry of monocytes to clean up thedebris is delayed. Fibroblasts also enter the local tissue to replacethe extracellular matrix and collagen. The process of tissue repair isstringently controlled within the tissue site. If the process becomesdysregulated, inappropriate tissue repair will lead to excessivescarring. Depending on the tissue and the intensity/duration of theinflammatory condition, the amount of scarring can be significant.

An example of disorders that vessel inflammation is involved isvulnerable plaque (VP) rupture. Previous studies have demonstrated thatinflammation promotes proliferation at sites of balloon angioplasty andstent placement in pigs (Komowski, et al., Coron Artery Dis. 12(6):513-5(2001)). Since sites of vulnerable plaque have a higher density ofmacrophages and lymphocytes than other types of atherosclerotic lesions,it is expected that these sites, when stented, will produce elevatedamounts of the cytokines (IL-1, TNF-alpha) that promote smooth musclecell proliferation.

Another example of disorders that vessel inflammation is involved isdiabetes. Studies have shown that patients with type-2 diabetes havehigher rates of restenosis than the general population. The diabeticpatient is in pro-inflammatory state that can amplify restenosis becausediabetic lesions contain a large number of inflammatory cells (e.g.,macrophages, lymphocytes, etc.).

Anti-Proliferative Agents

Any drugs having anti-proliferative effects can be used in the presentinvention. The anti-proliferative agent can be a natural proteineousagent such as a cytotoxin or a synthetic molecule. Preferably, theactive agents include antiproliferative substances such as actinomycinD, or derivatives and analogs thereof (manufactured by Sigma-Aldrich1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGENavailable from Merck) (synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁), alltaxoids such as taxols, docetaxel, and paclitaxel, paclitaxelderivatives, all olimus drugs such as macrolide antibiotics, rapamycin,everolimus, structural derivatives and functional analogues ofrapamycin, structural derivatives and functional analogues ofeverolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone,prodrugs thereof, co-drugs thereof, and combinations thereof.Representative rapamycin derivatives include40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,prodrugs thereof, co-drugs thereof, and combinations thereof.

In one embodiment, the anti-proliferative agent is everolimus.Everolimus acts by first binding to FKBP12 to form a complex (Neuhhaus,P., et al., Liver Transpl. 2001 7(6):473-84 (2001) (Review)). Theeverolimus /FKBP 12 complex then binds to mTOR and blocks its activity(Id.). By blocking mTOR activity, cells are unable to pass through GI ofthe cell cycle and as a result, proliferation is inhibited. mTORinhibition has also been shown to inhibit vascular smooth musclemigration.

Anti-Inflammatory Agents

Any drugs having anti-inflammatory effects can be used in the presentinvention. The anti-inflammatory drug can be a steroidalanti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, deflazacort, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

In one embodiment, the anti-inflammatory agent is clobetasol. Clobetasolis a corticosteroid that binds to corticosteroid receptors, a class ofnuclear receptor. The binding of clobetasol to the corticosteroidreceptor subsequently alters gene expression in such a way thatinflammation is inhibited. For example, corticosteroids inhibit theactivation of NFkB, the nuclear factor that is responsible for changesin gene expression that promote inflammation. The reduction ininflammation may also inhibit the mechanisms that promote small musclecell (SMC) hyper proliferation. This is shown in that dexamethasone, aless potent glucocorticoid as compared to clobetasol, reduces theproduction of PGDF and thus has anti-proliferative properties.Clobetasol acts through similar pathways and is more potent thandexamethasone.

Dosage

The dosage or concentration of the anti-proliferative andanti-inflammatory agents required to produce a favorable therapeuticeffect should be less than the level at which the bioactive agentproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of theagents required can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies.

In one embodiment, the bioactive agents can be incorporated intopolymeric coating in a percent loading of between about 0.01% and lessthan about 100% by weight, more preferably between about 5% and about50% by weight of the total drug-load that includes greater than about 0%to about 100% of the anti-proliferative agent and less than about 100%to greater than about 0% of the anti-inflammatory agent. The relativeamount of the anti-proliferative agent and anti-inflammatory agent canbe determined by the type of lesions to be treated. For example, whereeverolimus is used as the anti-proliferative agent and clobetasol isused as the anti-inflammatory agent, the relative amount of everolimusand clobetasol can be varied for different types of lesions, that is,the relative amount of everolimus can be higher for more proliferativelesions, and on the other hand, the relative amount of clobetasol can behigher for more inflammatory lesions.

Other Bioactive Agents

In some embodiments, other agents can be used in combination with theanti-proliferative agent and the anti-inflammatory agents: Thesebioactive agents can be any agent which is a therapeutic, prophylactic,or diagnostic agent. These agents can also have anti-proliferativeand/or anti-inflammmatory properties or can have other properties suchas antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant aswell as cystostatic agents. Examples of suitable therapeutic andprophylactic agents include synthetic inorganic and organic compounds,proteins and peptides, polysaccharides and other sugars, lipids, and DNAand RNA nucleic acid sequences having therapeutic, prophylactic ordiagnostic activities. Nucleic acid sequences include genes, antisensemolecules which bind to complementary DNA to inhibit transcription, andribozymes. Some other examples of other bioactive agents includeantibodies, receptor ligands, enzymes, adhesion peptides, blood clottingfactors, inhibitors or clot dissolving agents such as streptokinase andtissue plasminogen activator, antigens for immunization, hormones andgrowth factors, oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax a (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of such cytostatic substance includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford,Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® fromMerck & Co., Inc., Whitehouse Station, N.J.). An example of anantiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,and genetically engineered epithelial cells. The foregoing substancesare listed by way of example and are not meant to be limiting. Otheractive agents which are currently available or that may be developed inthe future are equally applicable.

Delivery Formulations

The composition comprising both anti-proliferative agent and theanti-inflammatory agent can be formulated into any formulation suitablefor delivery by any mode of delivery. For example, the composition canbe formed into a coating on an implantable medical device to providecontrolled release of the anti-proliferative agent and theanti-inflammatory agent. The composition can also be formulated intoother suitable formulations for example, bolus dose of free drug,optionally with a fluoroscopic dye, bolus dose of gel-encapsulated drug.

The gel can be formed of a gel-forming material or polymer such ashyaluronic acid, carboxymethyl cellulose, pectin, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, sodiumcarboxymethylcellulose, hydroxyethylcellulose, polyethylene oxide,acacia, tragacanth, guar gum, xanthan gum, locust bean gum, Carbopol™acidic carboxy polymer, polycarbophil, polyethylene oxide,poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinylacetate) cross-linked with hydrolyzable bonds, water-swellable N-vinyllactams polysaccharides, natural gum, agar, agarose, sodium alginate,carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gumarabic, gum ghatti, gum karaya, arbinoglactan, amylopectin, gelatin,hydrophilic colloids such as carboxylmethyl cellulose gum or alginategum, including both non-crosslinked and crosslinked alginate gums, wherethe crosslinked alginate gums may be crosslinked with di- or trivalentions, polyols such as propylene glycol, or other crosslinking agents,Cyanamer™ polyacrylamides, Good-rite™ polyacrylic acid, starch graftcopolymers, Aqua-Keeps™ acrylate polymer, ester crosslinked polyglucan,and the like, and combinations thereof. Some of the gel-formingmaterials are discussed in U.S. patents, U.S. Pat. Nos. 3,640,741,3,865,108, 3,992,562, 4,002,173, 4,014,335, and 4,207,893. Hydrogelsalso are discussed in the Handbook of Common Polymers, by Scott andRoff, published by the Chemical Rubber Company, Cleveland, Ohio. For anygiven gel-forming material or polymer, use of a material with higheraverage molecular weight provides higher viscosity in aqueous solutionof any given concentration. Therefore, using a higher molecular weightgenerally enables use of a lesser quantity of polymer to accomplish therequired retardation of dissolution. In some embodiments, thegel-forming material or polymer can be hydropropyl methylcellulosehaving 19-24% methoxyl substitution and 7-12% hydroxypropyl substitutionand a number average molecular weight of at least 20,000. Such polymersinclude those sold by Dow Chemical Co. under the tradenames MethocelK4M, Methocel K15M and Methocel K100M.

Modes of Delivery

In one embodiment, the anti-inflammatory drug such as clobetasol isformulated into a bolus dose of free drug with, optionally, afluoroscopic dye. The anti-proliferative drug such as everolimus can beformulated into a coating composition with a polymeric material and thencoated onto an implantable device (e.g., stent). The bolus dose ofanti-inflammatory drug is administered first and then theanti-proliferative drug is delivered by release from the implantabledevice such as a drug-delivery stent. The composition may furtherinclude a third agent such as a HDL (high density lipoprotein)-mimic asdescribed in U.S. Pat. No. 6,367,479. Alternatively, HDL-mimic can bedelivered by the stent.

In another embodiment, the anti-inflammatory drug such as clobetasol isformulated into a bolus dose of gel. The anti-proliferative drug such aseverolimus can be formulated into a coating composition with a polymericmaterial and then coated onto an implantable device. The bolus dose ofthe anti-inflammatory drug is administered first and then theanti-proliferative drug is delivered by release from the implantabledevice such as a drug-delivery stent.

In a further embodiment, the anti-inflammatory drug and theanti-proliferative drug can be included in a polymeric matrix and thencoated onto a medical device such as a stent. The medical device coatingcan be designed to have a variety of different release parameters foreach of the drugs included in the coating. For example, theanti-inflammatory can have one or a combination of release profiles thatinclude a pulse release, fast or burst release, and a sustained release.Similarly, the anti-proliferative drug can have one or a combination ofrelease profiles that include a pulse release, fast or burst release,and a sustained release from the stent. In some embodiments, thecombination can be delivered simultaneously or at least during the drugtreatment period there is at lease some overlap between the release ofthe drugs. In some embodiments, the anti-inflammatory can be completelyreleased prior to the release to the anti-proliferative or can bepartially released with some or significant overlap between the releaseof both drugs. “Pulse release” generally refers to a release profile ofa drug that features a sudden surge of the release rate of the drug. Therelease rate surge of the drug would then disappear within a period. Amore detailed definition of the term can be found in Encyclopedia ofControlled Drug Delivery, Edith Mathiowitz, Ed., Culinary andHospitality Industry Publications Services.

As used herein, the term “fast release” in one embodiment refers to arelease profile of a drug that features a release rate in the rangebetween about 15 to about 40 μg per day for a 18 mm stent, about 10 μgto about 27 μg per day for a 13 mm stent, and about 6.7 μg to about 17.2μg per day for a 8 mm stent. Equivalent profiles can be derived by onehaving ordinary skill in the art for stents having other sizes. Inanother embodiment, the term “fast release” refers to an approximately20% release in 24 hours of a drug. The term “fast release” is usedinterchangeably with the term “burst release.”

As used herein, the term “sustained release” generally refers to arelease profile of a drug that can include zero-order release,exponential decay, step-function release or other release profiles thatcarry over a period of time, for example, ranging from several days toseveral years. The terms “zero-order release”, “exponential decay” and“step-function release” as well as other sustained release profiles arewell known in the art (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality IndustryPublications Services).

In one embodiment, at least one of the anti-inflammatory agent (e.g.,clobetasol) and anti-proliferative agent (e.g., everolimus) isadministered via a stent while the other is administered by other localmeans of administration or alternatively, the other is administeredsystemically. In other embodiments, both are administered locally, bymeans other than a stent, or alternatively systemically. Systemicadministration can be accomplished orally or parenterally includingintravascularly, rectally, intranasally, intrabronchially, ortransdermally. Liquid carriers which are sterile solutions orsuspensions can be injected intramuscularly, intraperitoneally,subcutaneously, and intravenously. Rectal administration can be in theform of conventional suppository. For adminsitration by intranasal orintrabronchial inhalation or insufflation, the drug can be formulatedinto an aqueous or partially aqueous solution, which can then beutilized in the form of an aerosol. The drug can be administeredtransdermally through the used of a transdermal patch and a carrier thatis inert to and mutually compatible with the active component, isnon-toxic to the skin, and allows for the delivery of the drug forsystemic absorption into the blood stream via the skin. The carrier maytake any number of forms such as creams, ointments, pastes, and gels.The creams and ointments may be viscous liquids or semisolid emulsionsof either the oil-in-water or water-in-oil type. Pastes made ofabsorptive powders dispersed in petroleum or hydrophilic petroleumcontaining the active component may also be suitable. Other devicescapable of releasing the drug into the blood stream includesemi-permeable membranes covering a reservoir containing the drug, withor without a carrier.

Local administration can be accomplished by a variety of techniqueswhich administer the active component at or near the target site. Thefollowing examples of local delivery techniques are provided forillustrative purposes and are not intended to be limiting. Examplesinclude local delivery catheters, site specific carriers, implants,direct application, or direct injection. Local delivery by a catheterallows for the administration of the drug directly to the target site.

Local delivery by site specific carriers is conducted by attaching thedrug to a carrier which will direct or link the drug to the targetcells. Examples of this delivery technique include the use of carriersuch as a protein ligand, a monoclonal antibody or a membrane anchoredlinker.

Local delivery by an implant (other than a stent) is the placement of amatrix carrying the drug at the site. The matrix can release the activecomponent by, for example, diffusion, degradation, chemical reaction,solvent activators, etc. One example of local delivery by an implant caninclude direct injection of vesicles or micro-particles. Thesemicro-particles may be composed of substances such as proteins, lipids,carbohydrates or synthetic polymers. The micro-particles can have thedrug impregnated therein and/or coated thereon. Application via implantsis not limited to the above described routes and other techniques suchas grafts, micropumps or application of a fibrin glue or hydrogelcontaining the active component around the exterior of a designatedregion of the vessel can also be implemented by one of ordinary skill inthe art.

Local delivery by direct injection describes injecting a liquid carriercontaining the drug directly into the site. The liquid carrier should beinert to and mutually compatible with the drug. The component can be intrue solution or suspended in fine particles in the carrier. A suitableexample of an inert carrier includes a sterile saline solution.

Biocompatible Polymers

Any biocompatible polymers can be used to form a coating on a stent orto provide a drug delivery particle with the anti-proliferative drugand/or anti-inflammatory drug. Such biocompatible, bioabsorbablepolymers include, but not limited to, poly(ester amide), poly(esteramide) that may contain alkyl groups, amino acid groups, orpoly(ethylene glycol) (PEG) groups, polyethylene glycol (PEG),polylakanoates (PHA), poly(2-hydroxyalkanoates),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalknaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers comprising any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, polyesters, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone,poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(phosphoesters),polyphosphazenes, poly(amino acids), polysaccharides, collagen,chitosan, alginate, polyethers, polyamides, polyurethanes,polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropyleneoxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP),alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA),alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOHor EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™ polymers such aspoly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) andpoly(vinylidene fluoride) (PVDF) and combinations thereof.

Method of Coating A Device

The coating described herein can be formed by spray coating or any othercoating process available in the art. Generally, the coating involvesdissolving or suspending the composition, or one or more componentsthereof, in a solvent or solvent mixture to form a solution, suspension,or dispersion of the composition or one or more components thereof,applying the solution or suspension to an implantable device, andremoving the solvent or solvent mixture to form a coating or a layer ofcoating. Suspensions or dispersions of the composition described hereincan be in the form of latex or emulsion of microparticles having a sizebetween 1 nanometer and 100 microns, preferably between 1 nanometer and10 microns. Heat and/or pressure treatment can be applied to any of thesteps involved herein. In addition, if desirable, the coating describedhere can be subjected to further heat and/or pressure treatment. Someadditional exemplary processes of coating an implantable device that maybe used are described in, for example, Lambert T L, et al. Circulation,1994, 90: 1003-1011; Hwang C W, et al. Circulation, 2001; 104: 600-605;Van der Giessen W J, et al. Circulation, 1996; 94: 1690-1697; Lincoff AM, et al. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, JAmerican College Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster1174-15; Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L,et al. Z Kardiol, 2003, 92: 10, 825-832; and Tanabe K, et al.Circulation 2003, 107: 4, 559-64.

As used herein, the term “solvent” refers to a liquid substance orcomposition that is compatible with the polymer and is capable ofdissolving or suspending the polymeric composition or one or morecomponents thereof at a desired concentration. Representative examplesof solvents include chloroform, acetone, water (buffered saline),dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,)iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol,tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide(DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane,nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate,isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene,1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethylphosphoramide and a combination thereof.

Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation, Santa Clara, Calif.). The underlying structureof the device can be of virtually any design. The device can be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In one embodiment, the implantabledevice is a stent, which can be degradable stents, biodurable stents,depot stents, and metallic stens such as stents made of stainless steelor nitinol. The stents can be balloon expandable or self expanding.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will be retained on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, thrombosis, and restenosis. Stents may be placed ina wide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

The implantable device comprising a coating described herein can be usedto treat an animal having a condition or disorder that requires atreatment. Such an animal can be treated by, for example, implanting adevice described herein in the animal. Preferably, the animal is a humanbeing. Exemplary disorders or conditions that can be treated by themethod disclosed herein include, but not limited to, thrombosis, highcholesterol, hemorrhage, vascular dissection or perforation, vascularaneurysm, vulnerable plaque, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, restenosis andprogression of atherosclerosis in patient subsets including type Idiabetics, type II diabetics, metabolic syndrome and syndrome X,vulnerable lesions including those with thin-capped fibroatheromatouslesions, systemic infections including gingivitis, hellobacteria, andcytomegalovirus, and combinations thereof.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples. All parameters and data are not to beconstrued to unduly limit the scope of the embodiments of the invention.

Example 1 Porcine Implant Study

Described in this example is a 28 day porcine implant study thatcompared the 200 μg/cm² dose Lemans with a clobetasol-only deliverystent, an everolimus-only stent, and an everolimus-clobetasolcombination drug delivery stent. The study was performed using threedifferent drug delivery stents, Arm 1, Arm 2, and Arm 3. Arm 1 is Lemansstent (a stent available from Guidant based on PVDF-co-HFP) thatincluded 105 μg everolimus and used as a control. Arm 2 was loaded with185 μg clobetasol only, with no everolimus. Arm 3 is loaded with 105 μgeverolimus and 80 μg clobetasol.

The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretchmodel. Nine samples of each Arm stent were implanted, one for eachcoronary artery. 24 hr Release in porcine serum data were gathered. 3, 7and 28 day in vivo release data were gathered (from the mammaryarteries), as was 28 day quantitative coronary angioplasty (QCA),histology and morphometry.

In this study, 12 mm Vision Small stents (available from Guidant) wereused. All drug solutions were sprayed in a 2% Solef™ inacetone/cyclohexanone formulation. All stents had a 100 μg PBMA primer.Table 1 shows the coating design of the stents used in this study. TABLE1 Coating design Polymer Evererolimus Clobetasol Solid Target Drug (D)(P) D:P Drug % Target (μg) Target (μg) (μg) Arm 1 Everolimus Solef ™1:3   25.0 105 — 420 Arm 2 Clobetasol Solef ™ 1:4.2  19.2 — 185 962 Arm3 Ever & Clob Solef ™ 1:3.49 22.2 105  80 833

The release rate data are shown in Table 2. As can be seen from Table 2,a coating based on Solef™ is capable of simultaneous release of botheverolimus and clobetasol. TABLE 2 Release rate data In vivo In vivo Invivo In vitro In vivo In vivo In vivo In vitro Day 3 Day 7 Day 28 24 hrDay 3 Day 7 Day 28 24 hr % % % % % % % % Clobetasol ClobetasolClobetasol Clobetasol Everolimus Everolimus Everolimus EverolimusRelease Release Release Release in Release Release Release Release inArm (n = 2) (n = 3) (n = 4) PS (n = 3) (n = 2) (n = 3) (n = 4) PS (n =3) 1 - Everolimus 37.6% 49.3% 66.7% 30.0% 2 - Clobetasol 32.5% 43.1%60.6% 26.7% 3 - Everolimus +   Clobetasol 40.9% 50.2% 71.9% 30.1% 35.1%43.6% 60.4% 24.8%

The results of 28 day QCA are shown in FIG. 1, the 28 day histology dataare in FIG. 2, and the 28 day morphometry data are shown in FIG. 3 andsummarized in Table 3 below. TABLE 3 28 Day morphometry data from FIG. 3AVERAGE STANDARD DEVIATION Media Neointimal Media Neointimal NeointimalArea Neointimal % Thickness Injury Area Area % Thickness Injury(mm{circumflex over ( )}2) Area (mm{circumflex over ( )}2) Stenosis (mm)Score (mm{circumflex over ( )}2) (mm{circumflex over ( )}2) Stenosis(mm) Score Everolimus 1.21 1.81 27.83 0.28 1.83 Everolimus 0.23 0.7213.18 0.11 0.23 Clobetasol 1.09 1.73 24.86 0.29 1.79 Clobetasol 0.181.57 23.27 0.23 0.22 Clobetasol/ 0.97 0.82 12.39 0.14 1.62 Clobetasol/0.18 0.39  7.54 0.04 0.29 Everolimus Everolimus

The p values from a t-test of the data from FIG. 3 are summarized inTable 4. A “t-test” returns the probability associated with a Student'st-Test that determines whether two samples are likely to have come fromthe same two underlying populations that have the same mean. The valuereturned from the test, “p”, is the probability that the two groups ofdata come from the same population. p Values less than or equal to 0.10or 0.05 are generally considered significant (Zar, J H. BiostatisticalAnalysis. Englewood Cliffs, N.J.: Prentice-Hall Inc, 1974. pp 101-108).TABLE 4 p Values from a t-test of the data from FIG. 3 Neointi- Neointi-Media mal % mal Injury Arm Comparison Area Area Stenosis Thickness ScoreEVER COMBO 0.05 0.01 0.02 0.01 0.18 EVER CLOB 0.29 0.90 0.77 0.93 0.78COMBO CLOB 0.24 0.18 0.22 0.14 0.25

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A drug-delivery system, comprising an effective amount of everolimus,or derivatives thereof, and an effective amount of clobetasol for thetreatment or prevention of a vascular disorder or a related disorder. 2.The drug-delivery system of claim 1, wherein the system is a stent. 3.The drug-delivery system of claim 1, wherein the disorder is restenosis.4. The drug-delivery system of claim 1, wherein the disorder isrestenosis and/or progression of atherosclerosis in patient subsetsincluding type I diabetics and type II diabetics.
 5. The drug-deliverysystem of claim 1, wherein the disorder is vulnerable plaque.
 6. Thedrug-delivery system of claim 1, wherein the system is a polymer or apolymeric coating.
 7. A drug-delivery system, comprising an effectiveamount of everolimus, rapamycin, or derivatives of everolimus orrapamycin, and an effective amount of a steroidal anti-inflammatoryagent or a non steroidal anti-inflammatory agent, wherein thecombination is for treatment or prevention of a vascular disorder. 8.The drug-delivery system of claim 7, wherein the anti-inflammatory agentis clobetasol.
 9. The drug-delivery system of claim 7, wherein thesystem is a stent.
 10. The drug-delivery system of claim 7, wherein thedisorder is restenosis.
 11. The drug-delivery system of claim 7, whereinthe disorder is restenosis and/or progression of atherosclerosis inpatient subsets including type I diabetics and type II diabetics. 12.The drug-delivery system of claim 7, wherein the disorder is vulnerableplaque.
 13. The drug-delivery system of claim 7, wherein the system is apolymer or a polymeric coating.
 14. A method of treating restenosis of ablood vessel comprising administering to a patient an effective amountof everolimus, rapamycin, or derivatives of everolimus or rapamycin andan effective amount of a steroidal anti-inflammatory agent or a nonsteroidal anti-inflammatory agent, wherein the combination is fortreatment or prevention of the vascular disorder.
 15. The method ofclaim 14, wherein the anti-inflammatory is clobetasol.
 16. The method ofclaim 14, wherein everolimus, rapamycin, or derivatives of everolimus orrapamycin is delivered via a stent and the anti-inflammatory isdelivered by other local means or by systemic means.
 17. The method ofclaim 14, wherein the combination of the drugs are administered by adrug-delivery stent.
 18. A method of treating vulnerable plaque of ablood vessel comprising administering to a patient an effective amountof everolimus, rapamycin, or derivatives of everolimus or rapamycin andan effective amount of a steroidal anti-inflammatory agent or a nonsteroidal anti-inflammatory agent, wherein the combination is fortreatment or prevention of the vascular disorder.
 19. The method ofclaim 18, wherein the anti-inflammatory is clobetasol.
 20. The method ofclaim 18, wherein everolimus, rapamycin, or derivatives of everolimus orrapamycin is delivered via a stent and the anti-inflammatory isdelivered by local means other than a stent or by systemic means. 21.The method of claim 18, wherein the combination of the drugs areadministered by a drug-delivery stent.